An arms race of sorts is happening right now amongst the pharmaceutical companies who are all trying to deliver ‘medically differentiated products’. Current drug formats are inflexible, in that they generally allow for a single activity. For example, a recombinant monoclonal antibody generally is designed and optimized to bind and inhibit a single target protein. For example, a small molecule drug is generally designed and optimized to bind and activate (or inhibit) a single target. In some cases, the drug is not selective and there are multiple activities (for example, a small molecule kinase inhibitor that is designed to bind the ATP binding site of a single kinase but which shows a level of affinity and bioactivity against adjacent kinase family members). But generally drug developers optimize using today's drug formats for single activities and non-selectivity is seen as something to engineer away in the drug development process.
In today's drug development, then, the selection of the single target is the key variable. Drugs, therefore, are developed from a format-centric point of view. But drugs are developed to treat disease. And diseases generally are composed of more than one pathophysiologic mechanism happening in series or in parallel. A mechanism being a pathway or set of intersecting pathways occurring either in a localized cell or tissue or organ or systemically throughout the organism. A pathway being a set of moieties that interact with each other. A more ideal way to engage in drug development is to be able to take a disease-centric or biology-centric approach. For example, based on the sum of academic and corporate and historical research and experience to date, disease x involves pathways a, b, and c. Within pathway a, target protein z is known to be upregulated (and could be bound and inhibited by an antibody fragment). Within pathway b, cell-type y is known to be proliferating inappropriately (and could be impacted by a small molecule anti-proliferative agent). And the pathophysiology of pathway a and b is occurring within tissue subtype x (and which could be targeted or enriched with drug by including on the drug several copies of a small tissue-targeting peptide). It would be ideal to have a drug technology or format that allowed these multiple functions and different types of bioactive moieties (protein, oligonucleotide, small molecule, lipid, etc.) to be integrated into a single, adaptable, multi-functional drug that is a practical best-of-breed and straightforward in its design, implementation, manufacturing, and administration. In addition, the technology should allow for certain of the bioactive moieties to be unstably attached such that they can be released under the desired conditions (time, aqueous pH environment, other). These drugs should demonstrate higher efficacy and safety while providing a higher overall probability of technical, regulatory, and commercial success from early in the drug development process.
Most diseases are complex and multifactorial in origin. Therefore, in applying this biology-centric or disease-centric approach, one could imagine a future ten or fifteen years down the road where a big disease such as rheumatoid arthritis is actually divided through diagnostic (molecular, imaging, biomarker, genetic) or other approaches into, say, ten major subtypes each of which is driven by a particular set of pathophysiologies and which can be targeted using one multi-functional drug such that ten multi-functional drugs are developed in order to treat the ten different disease types.
The present invention describes such a drug technology format that can be the backbone of the next-generation of multi-functional drug development. The technology delivers a polymer backbone which (i) itself delivers fundamental biocompatibility to the drug through the selection of hydrophilic monomer and architecture, and (ii) also forms a core backbone for conjugation and/or adsorption to multiple agents of different types (amino acid, small molecule, oligonucleotide, lipid, other, diagnostic agent, imaging agent, therapy monitoring agent), predefined stoichiometries and functions (biocompatibility, spacer, bioactivity, targeting, diagnostic, imaging, other), and (iii) can employ any stable or flexible (under predefined conditions) conjugation chemistry.
Hydrophilic polymers for drug conjugation have been well described and the drug conjugates are generating in excess of $5 billion revenue per annum. What is important for these polymers is the extent to which they bind water molecules and the physical properties of those water binding interactions. This combination of properties drives the fundamental biocompatibility of the polymer. PEG is one example of a hydrophilic polymer, but there are other examples of hydrophilic polymers that bind water to a different extent and with different physical properties and therefore with different fundamental biocompatibility. One such example is phosphorylcholine-based polymers, specifically polymers derived from 2-methacryloyloxyethyl phosphorylcholine, which polymers have been commercialized in various forms in medical devices such as coronary drug eluting stents and contact lenses. In recent years, new methods of controlled radical polymerization have been developed with the promise to enable the manufacture of large, complex-architecture polymers with low cost and high quality.
The present invention integrates a drug technology and format that allows for a new paradigm of drug development, starting with a set of biologies driving disease pathophysiology; integrating biocompatibility moieties, drug moieties of different classes, extended architectures, flexible chemistries, all in a practical package. More simply put, the present invention presents a drug format that allows the user to create a nanoscale biomachine with the goal of creating magic bullets for combating diseases to the benefit of patients.
Efforts to formulate biologically active agents for delivery must deal with a variety of variables including the route of administration, the biological stability of the active agent and the solubility of the active agents in physiologically compatible media. Choices made in formulating biologically active agents and the selected routes of administration can affect the bioavailability of the active agents. For example, the choice of parenteral administration into the systemic circulation for biologically active proteins and polypeptides avoids the proteolytic environment found in the gastrointestinal tract. However, even where direct administration, such as by injection, of biologically active agents is possible, formulations may be unsatisfactory for a variety of reasons including the generation of an immune response to the administered agent and responses to any excipients including burning and stinging. Even if the active agent is not immunogenic and satisfactory excipients can be employed, biologically active agents can have a limited solubility and short biological half-life that can require repeated administration or continuous infusion, which can be painful and/or inconvenient.
For some biologically active agents a degree of success has been achieved in developing suitable formulations of functional agents by conjugating the agents to water soluble polymers. The conjugation of biologically active agents to water soluble polymers is generally viewed as providing a variety of benefits for the delivery of biologically active agents, and in particular, proteins and peptides. Among the water soluble polymers employed, polyethylene glycol (PEG) has been most widely conjugated to a variety of biologically active agents including biologically active peptides. A reduction in immunogenicity or antigenicity, increased half-life, increased solubility, decreased clearance by the kidney and decreased enzymatic degradation have been attributed to conjugates of a variety of water soluble polymers and functional agents, including PEG conjugates. As a result of these attributes, the polymer conjugates of biologically active agents require less frequent dosing and may permit the use of less of the active agent to achieve a therapeutic endpoint. Less frequent dosing reduces the overall number of injections, which can be painful and which require inconvenient visits to healthcare professionals. Conjugation of PEG or other polymers can also modify the core activity of the drug itself—the idea of “additional bioactivities conferred to the drug by virtue of polymer conjugation (for example, the large hydrodynamic radius broadens the scope of inhibition from drug (antibody fragment) inhibits binding to receptor A but polymer-drug conjugate inhibits binding to receptor A plus receptor B as a function of any number of different mechanisms but certainly steric hindrance.
Although some success has been achieved with PEG conjugation, “PEGylation” of biologically active agents remains a challenge. As drug developers progress beyond very potent agonistic proteins such as erythropoietin and the various interferons, the benefits of the PEG hydrophilic polymer are insufficient to drive the increases in solubility, stability and the decreases in viscosity and immunogenicity that are necessary for a commercially successful product that is subcutaneously administered. PEG conjugation may also result in the loss of biological activity. A variety of theories have been advanced to account for loss of biological activity upon conjugation with PEG. These include blockage of necessary sites for the agent to interact with other biological components, either by the conjugation linkage or by the agent being buried within the PEG conjugate, particularly where the polymer is long and may “wrap” itself around some of the active agent, thereby blocking access to potential ligands required for activity.
Branched forms of PEG for use in conjugate preparation have been introduced to alleviate some of the difficulties encountered with the use of long straight PEG polymer chains. While branched polymers may overcome some of the problems associated with conjugates formed with long linear PEG polymers, neither branched nor linear PEG polymer conjugates completely resolve the issues associated with the use of conjugated functional agents. Both linear and branched PEG conjugates can, for example, suffer from rates of degradation that are either too long or too short. A rapid rate of degradation can result in a conjugate having too short of an in vivo half-life, whereas, too slow of a rate of degradation can result in an unacceptably long conjugate half-life in vivo.
In view of the recognized advantages of conjugating functional agents to water soluble polymers, and the limitations of water soluble polymers such as PEG in forming conjugates suitable for therapeutic purposes, additional water soluble polymers for forming conjugates with functional agents are desirable. Water soluble polymers, particularly those which have many of the advantages of PEG for use in conjugate formation, and which do not suffer from the disadvantages observed with PEG as a conjugating agent would be desirable for use in forming therapeutic and diagnostic agents. To this end, polymers of 2-methacryloyloxyethyl-phosphorylcholine are set forth for use in preparing conjugates of biologically active agents.